Patients with schizophrenia are at risk for obesity due to inactive lifestyles, and the effects of antipsychotic medications, and they are also at high risk for the metabolic syndrome, with prevalence rates twice that for age matched cohorts. A core feature of the metabolic syndrome is central adiposity. Recent data suggest that schizophrenia patients have a tendency to store excess fat intraabdominally, a tendency that is fully expressed in those exposed to a western diet, and is associated with a deleterious impact on insulin sensitivity and coronary heart disease risk. An NIMH-funded study of intensive behavioral therapy for obese patients with schizophrenia has commenced, but this modality is not widely available to schizophrenia patients, leaving clinicians with few proven options to address obesity. Recent data demonstrate that certain atypical antipsychotics are relatively weight neutral, and that switching may result in significant weight loss, but this data lacks sophisticated measures of body composition or insulin sensitivity to explore the total extent of health improvement. The Candidate has demonstrated a significant interest in the health of schizophrenia patients, and will use the proposed award to become one of the few psychiatric researchers with endocrinology training needed to study the biological basis for metabolic dysfunction seen in patients with schizophrenia. This K23 award will allow the Candidate to develop expertise in techniques for studying glucose/insulin homeostasis and body composition, and apply such knowledge in the context of a prospective, randomized study of antipsychotic switch to a relatively weight neutral antipsychotic vs. usual care for obese, nondiabetic schizophrenia patients. The proposed outcome measures will include direct measurement of changes in serum lipids, visceral adiposity (by imaging) and insulin sensitivity. The Candidate also intends to develop expertise in the study of complex genetic disorders as part of the didactic program set forth in the grant, and combine that knowledge with the data from the proposed study to design future studies focusing on the genetics of metabolic dysfunction in patients with schizophrenia. The Candidate will combine and extend the knowledge of the two Cosponsors in this area of metabolic disturbances among schizophrenia patients, and will specifically analyze the relative impact of a viable treatment option (antipsychotic switch) for obese schizophrenia patients. These goals also support the NIH Roadmap initiatives in building cross disciplinary research, and developing interdisciplinary investigators who can tackle complex clinical problems such as metabolic dysfunction among the severely mentally ill.